Clear aqueous antacid solution containing a polymeric meglumine-hexitol-aluminum hydroxide complex and preparation thereof

ABSTRACT

Aqueous antacid solution comprising water and an effective amount of a polymeric meglumine-hexitol-aluminum hydroxide complex having mole ratios of Al:hexitol:meglumine of about 1:at least 0.333:0.12-0.50, preferably 1:0.667-1.333:0.20-0.333, is prepared by reacting aluminum tri(lower-alkoxide) in a non-polar solvent with an aqueous solution of meglumine and hexitol, removing the solvent and lower-alkanol formed by the reaction, and diluting the remaining aqueous solution with water to the desired concentration. A preferred modification having up to about 27 percent by weight of the aluminum hydroxide replaced by magnesium hydroxide is prepared as above by replacing a portion of the aluminum tri-(lower-alkoxide) by magnesium di-(loweralkoxide) or by magnesium di-aluminum octa-(lower-alkoxide).

United States Patent [1 1 Hinkel, Jr.

[ CLEAR AQUEOUS ANTACID SOLUTION CONTAINING A POLYMERIC MEGLUMlNE-HEXITOL-ALUMINUM HYDROXIDE COMPLEX AND PREPARATION THEREOF [75] Inventor: Emil T. Hinkel, Jr., Bethlehem,

[73] Assignee: Sterling Drug Inc., New York, NY.

[22] Filed: July 5, 1973 [21] Appl. No.: 376,349

Related US. Application Data [63] Continuation-impart of Ser. No. 152,963, June 14,

1971, abandoned.

[52] US. Cl. 424/157; 424/317; 424/325; 424/343 [51] Int. Cl A61k 27/00 [58] Field of Search 424/157, 158, 180, 343, 424/325, 317

[56] References Cited UNITED STATES PATENTS 2,451,772 10/1948 Plunglan 424/180 3,245,876 4/1966 Martin, 1!. 424/157 July 1,1975

3,519,712 7/1970 Newmark 424/180 3,655,883 4/1972 Granatek et al. 424/157 3,735,007 5/1973 Lapidus et a1. 424/158 Primary Examiner-Frederick E. Waddell Attorney, Agent, or Firm-Robert K. Bair; B. Woodrow Wyatt [57] ABSTRACT Aqueous antacid solution comprising water and an effective amount of a polymeric meglumine-hexitolaluminum hydroxide complex having mole ratios of Alzhexitolzmeglumine of about lzat least 0.333:0.12-0.50, preferably 1:0.6671.333:0.20 0.333, is prepared by reacting aluminum tri(loweralkoxide) in a n0n-polar solvent with an aqueous solution of meglumine and hexitol, removing the solvent and lower-alkanol formed by the reaction, and diluting the remaining aqueous solution with water to the desired concentration, A preferred modification having up to about 27 percent by weight of the aluminum hydroxide replaced by magnesium hydroxide is prepared as above by replacing a portion of the aluminum tri- (lower-alkoxide) by magnesium di-(lower-alkoxide) or by magnesium di-aluminum octa-(lower-alkoxide).

20 Claims, No Drawings CLEAR AQUEOUS ANTACID SOLUTION CONTAINING A PLOYMERIC MEGLUMlNE-I-IEXITOL-ALUMINUM HYDROXIDE COMPLEX AND PREPARATION THEREOF This application is a continuation-in-part of my copending application Ser. No. 152,963, filed June 14, 1971 and now abandoned. I

This invention relates to aqueous antacid compositions comprising aluminum hydroxide or aluminum hydroxide-magnesium hydroxide and to their preparation.

Many aqueous antacid and/or ulcer treating compositions comprising aluminum hydroxide have been formulated as suspensions over the past 40 years; also, a number of corresponding preparations comprising the combination of aluminum hydroxide and magnesium hydroxide have been prepared over the past 20 years. These suspensions have the disadvantages of physical unstability, lack of homogeneity, poor palatability and great variation in viscosity.

The composition aspect of the the invention does not have these disadvantages of the said known suspensions and, further, has other advantages, thereby resulting in a unique combination of desirable properties in the novel aqueous antacid solution of the invention.

The invention, in its composition aspect, resides in a clear aqueous solution comprising water and an effective amount, preferably from about 20 to 45 percent by weight per volume, of a polymeric meglumine-hexitolaluminum hydroxide complex which has mole ratios of Alzhexitolzmeglumine of about lzat least 0.333:0.l2-0.50, preferably, l:0.667-l.333:0.- 200.333. A preferred modification of this composition is the solution where up to about 27 percent by weight of the aluminum hydroxide is replaced by magnesium hydroxide. A preferred embodiment is the aqueous antacid solution comprising a polymeric megluminehexitol-aluminum hydroxide complex or a polymeric meglumine-hexitol-aluminum hydroxide-magnesium hydroxide complex containing about 4.5 to 9.0 percent of aluminum as aluminum hydroxide, from to about 3.0 percent of magnesium as magnesium hydroxide, about 2.25 to 4.5 percent of meglumine, about to 30 percent of sorbitol, and from 0 to about 7.0 percent of magnesium gluconate, each percentage being as weight per volume; a particularly preferred embodiment is said solution containing upper limits of about 6.0 percent of aluminum as aluminum hydroxide, about 1.5 percent of magnesium as magnesium hydroxide, about 3.0 percent of meglumine, about percent of sorbitol, and, optionally, about 3.5 percent of magnesium gluconate. Other solutions within the scope of the invention can contain as low as about l2 percent (as weight per volume) of said complex, either with or without magnesium as magnesium hydroxide, were obtained by diluting the aforesaid solutions with distilled water.

The aqueous antacid solution of the invention has the following unique combination of properties as determined by standard test procedures, presented hereinbelow: the solution is clear; it is palatable without the chalkiness and astringency of the conventional suspensions; its acid neutralizing capacity, at equal dosages, is equal to or superior to that of conventional commercial suspensions; its rapid speed of acid neutralization likewise equals or surpasses that of the conventional aluminum hydroxide or aluminum-magnesium hydroxide suspensions; it gives greater protection against stomach ulceration in animal tests than the conventional suspensions; it is indicated by animal tests to have a greater coating action on the stomach mucosa than the conventional suspensions; it is practically free of sodium ion, which is undesirable to patients with heart or kidney aliments, one teaspoon containing only 0.25 mg. of sodium compared to 2.5 mg. and more in the leading commercial suspensions; and, it is carbonate free in contrast with conventional suspension antacids which contain residual carbonate due to manufacturing procedures.

' The invention, in its process aspect, resides in the process for preparing a clear aqueous antacid solution comprising water and an effective amount, from about 12 to 45 percent and preferably from about 20 to 45 percent by weight per volume, of a polymeric meglumine-hexitol-aluminum hydroxide complex which has mole ratios of Al:hexitol:meglumine of about lzat least 0.333:0.12-0.50, preferably l:O.667l.333:0.- 20-0333, which comprises mixing aluminum tri- (lower-alkoxide) in a non-polar solvent with an aqueous solution of meglumine and hexitol, separating the aqueous phase from the non-polar phase of the mixture, heating the aqueous phase under reduced pressure to remove residual non-polar solvent and the lower-alkanol produced in the mixture, and diluting the remaining aqueous solution with water to the desired concentration. A preferred modification of this process is the preparation of said aqueous antacid solution where up to about 27 percent by weight of the aluminum hydroxide is replaced by magnesium hydroxide wherein the process is modified by replacing a portion of the aluminum tri-(lower-alkoxide) with magnesium di-(lower-alkoxide) or by magnesium di-aluminum octa-(lower-alkoxide). Because of their case of preparation and lower cost, preferred lower-alkoxides are the isopropoxides and n-propoxides, and, for the same reasons, the preferred hexitols are sorbitol and mannitol.

As used herein, the term lower-alkoxide means alkoxide moieties having from two to five carbon atoms inclusive and being straight or branched chained, among which are, for purposes of illustration but without limiting the generality of the foregoing, ethoxide, n-propoxide, isopropoxide, n-butoxide, isobutoxide, 2-butoxide and n-amoxide.

The manner and process of making and using the invention will now be generally described so as to enable a person skilled in the art of pharmaceutical chemistry to make and use the same, as follows:

The essential ingredients used to prepare the aqueous antacid solution of the invention are known compounds, for example, meglumine is N- methylglucamine, also known as l-deoxy-lmethylamino-D-glucitol or N-methyl-D-glucamine. As illustrative of hexitol, sorbitol, which is conveniently employed as an aqueous solution (e.g., percent), is also known as D-sorbitol, sorbit, sorbol, or D-glucitol and mannitol is also known as D-mannitol, mannite or manna sugar. The aluminum tri-(lower-alkoxides), magnesium di-(lower-alkoxides) and magnesium dialuminum octa-(lower-alkoxides) are known compounds prepared by conventional methods.

The aqueous antacid solution of the invention also can include one or more sweetening agents, e.g., saccharin, etc.; one or more flavoring agents, e.g., peppermint, etc.; and, one or more preservatives, e.g,, methyl or propyl 4-hydroxybenzoate, etc. Theuse of sweeten ing, flavoring and preserving agents is conventional and forms no part of the instant invention, and it is contemplated that any such compatible agents can be used.

The process aspect of the invention is carried out conveniently by mixing, preferably with stirring, at solution of aluminum tri-(lower-alkoxide), preferably aluminum isopropoxide or aluminum n-propoxide, in a non-polar solvent, for example, benzene, cyclohexane, and the like, with an aqueous solution containing the hexitol, preferably sorbitol or mannitol, meglumine and water. The reaction mixture is mixed well and allowed to stand until the non-polar and aqueous phases separate. The aqueous phase is separated from the nonpolar layer, e.g., by decantation of the latter. and washed with a non-polar solvent, e.g., benzene or cyclohexane, the washings being discarded Theaqueous phase is then heated in vacuo at about-40 to 70C., preferably about 50 to 60C.,to remove the non-polar solvent and the lower-alkanol pro duced by the reaction. e.g., isopropyl alcohol when using aluminum isopropoxide or n-propanol when using aluminum npropoxide. The remaining aqueous so lu tion is diluted to the desired concentration with distilled water. The resulting cloudy aqueous solution becomes clear on standing at room temperature about 22-26C.). The pH of the solution ranges from about 8.5 to 9.8..The aqueous solution of the invention containing up to about 27 percent by weight of the aluminum hydroxide replaced by magnesium hydroxide is prepared as above by replacing the calculated proportion of the aluminum tri-(lower-alkoxide) with magnesium d i-(loweralkoxide) or magnesium di-aluminum oct a-(loweralkoxide), preferably magnesium isopropoxide or npropoxide, or magnesium di-alumin'um o cta (isopropoxide) or octa-(n-propoxide). 1

Optionally, the magnesium content of the solution containing the polymeric meglumine-hexitol -alurninum hydroxide-magnesium hydroxide complex can'be increased by the addition of a suitable water soluble magnesium salt; e.g., magnesium gluconate, magnesium tartrate. and the like. I I i I The total acid neutralizing power (ANP) of the aqueous antacid solution of the invention was determined as follows: I Transfer 1.0 ml. (to contain pipet) of the solution to a 100 ml. volumetric flask. Add 50 ml. of water to the flask, using portions of the water to rinse the pipet. Add 10.0 ml. of 1N hydrochloric acid and mix. Heat at 37C. for 1 hour, shaking frequently. Cool to room temperature, dilute to volume (100 ml.) with water, and mix. Titrate 25.0 ml. potentio'metrically to pH with 0.1N sodium hydroxide. The total acid neutralizing power (ANP) is calculated as follows: l (4 ml.

Prepare a glass constant temperature cell at- 37C. and provide with electrodes and-stirrer. Add 40 ml. of water and, optionally, l0 dropsof a wetting agent, e.g., TritonX-l-OO or iso-octyl phenoxy polyethoxy ethanol. Bring to 37C. and add 3.0m]. (to contain pipet) of the antacid solution, using 10 ml. of water in several portions to rinse the pipet. Allow mixture to stir until thoroughly mixed and bring to 37+C. Turn on .pHmeter, start time and add 0.1N hydrochloric acid continuously at sucha rate as to maintain a pH of 3.5 Record the volume of acid consumed during each 2 /2 minute interval up to 15 minutes, and, if desired, during each 5 minute interval up to 30 minutes. When acid volume is plotted against time a smooth curve results. 7 I

The following examples will illustrate specific embodiments of the invention without, however, limiting it thereto. a v

EXAMPLE 1 I An aqueous antacid solution comprising polymeric meglumine-sorbitol-aluminum hydroxide complexhaving mole ratios of Alzsorbitokmeglumine of 1:1 33:0,20

was prepared as follows: To a well mixed solution" am- I ml.'of a solution containing 408 g. of aluminum. isopropoxide in .benzene also at room temperature! Stirring was. continued for 30 minutes after all ofthe aluminum isopropoxide solution had been. added-. 1 he solution was allowed to stand for about 1 hour and. the layers were separated by decanting the benzene layer. The aqueous layer was extracted with two,500 ml. portions of benzene and the benzene extracts discarded. The aqueous phase was then heated in vacuo to remove any remaining benzene and. the isopropyl alcohol formed by the reaction. The,remaining aqueous preparation wasdiluted with distilled water-to yield .26 00 g. of a cloudy. aqueous solution. On standing for about two weeks at room temperature, the solution became clear. The pH of the solution was.9.0,and its de nsity was 1.111. The quantity of the polymeric megluminesorbitol-aluminum hydroxide complex in the solution is calculated as equivalent to 6 percent aluminum hy-,

droxide, 18.6 percent sorbitol and 3.0 percent meglumine; analysis showed the solution to contain 6.00 percent aluminum hydroxide, 18.4 percent sorbitol and 3.19 percent meglumine. The amount of sodium found was 0.00055 percent. The total acid neutralizing power (ANP) of this solution after standing for one month at room temperature (r.t. about 23-25 ,C.) was found to be 25.6 of 0.1N HCl/inl. Its rate of acid neutralization (RAN) after standing at room temperature for 23 and 75 days was found to be as follows! RAN. 1 ml. at 0.1N HCl per 3.0 ml.

. at minutes 23 days. n. 19.8 27.6 32.7 37.2 39.8 42.4 46.6 49.0 52.1 752d ay is. m. 21.8 27.7 2910 31.7 33.8' 37.8 40.8 43.0

0.1N sodium hydroxide)=ml. 0.1N hydrochloric acid EXAMPLE '2 neutralized per milliliter of sample. I

The rate of acid neutralization (RAN) of the aqueous antacid solution of the invention was determined as follows:

An aqueous antacid solution comprising polymeric meglumine-sorbitol-aluminum hydroxide-magnesium hydroxide complex having mole ratios of AlzMgzsorbitolzmeglumine of 1:0.45:1.50:0.20 was prepared as follows: A 2.816 kg. portion dff/O percentsorbitol solution and 282 g. of meglumine were dissolved in 4.05 liters of distilled 'water contained in a suitable vessel preferably having a capacity of about percent greater than the batch size. To the sorbitol-meglumine solution was added with vigorous stirring 7.216 liters of 1.0M Al 0.45M Mg isopropoxide solution in cyclohexane (preparation given below), the stirring being sufficiently vigorous so as to maintain an intimate mixture of the aqueous and cyclohexane phases. Vigorous stirring was continued for to 60 minutes'after addition of the isopropoxide solution. Stirring was then stopped and the reaction mixture was allowed to stand until the cyclohexane and aqueousphases separated. The cyclohexane phase was then removed by decantation. The aqueous phase was extracted with 1500 ml of fresh cyclohexane and vigorously mixed for five to ten minutes. The mixture was allowed to separate and the cyclohexane phase removed by decantation. The cyclohexane extraction procedure was repeated twice and then sufficient distilled water was slowly added with efficient stirring to the aqueous 'phase to bring the batch to 75-100 percent of the final volume. The residual cyclohexane and by-product isopropyl alcohol were removed by distillation under reduced pressureiheating the reaction vessel in a water bath of about 5060C. The remaining aqueous preparation was diluted with distilled water to yield 12.5 liters of the desired aqueous solution. The pH of the solution was 9.5 andits specific gravity at 25C. was 1.096. Each teaspoon (5 ml.) of this solution contains:

The rate of acid neutralization (RAN) of this solution after three weeks at room, temperature (r.t., i.e., 2325C., as used here and hereinafter) is given as follows:

solved in cyclohexane and to the solution was added cyclohexane to bring the total volume to 11 liters, thereby yielding a solution which assayed as'2.1M Al 0.94M Mg isopropoxide. Dilution of 3436 mlaof this 2.1M Al 0.94M Mg isopropoxide solution with 3780 m1. of cyclohexane yielded7;2l6 liters of the 1.0M Al 0.45M Mg isopropoxide solution. 1 1

EXAMPLE 3 An aqueous antacid solution comprising polymeric meglumine-sorbitol-aluminum hydroxide-magnesium hydroxide complex-havingmole ratios-of 'Al:Mg:sorbitozmeglumine of 1:O.30; 1=.50:0.20 and also having 0.15 mole of magnesium gluconate per mole of Al was prepared following the procedure described in Example 2 with the following. variations: 7.214 liters of a 1.0M,Al 0.3M Mg isopropoxide, solution in cyclohexane (prepared by mixing'magnesiurn aluminum isopropoxide solution, aluminum isopropoxide solution and cyclohexane) was added to the sorbitol-meglumine aqueous solution and after extracting the reaction mix.- ture three times with cyclohexane, a 450 g. portion of magnesium gluconate dissolved in about 1.5 liters of warm (50C.) distilled water was added to'the aqueous phase of the reaction mixture. Sufficient distilled water was added to the stirred mixture to bring the batch to approximately 75percent of the final volume. The residual cyclohexane and by-produ'ct'isopropyl alcohol was distilled off under reduced pressure as in Example 2 and the remaining aqueous preparation was diluted with-distilled-water to yield 12.5 liters of the desired aqueous solution...Each teaspoon-(Sml) of the solution contains: 9 1

av Refer to analysis of Example 29 \\'hicl1 is the same as Example 3.

The pH of the solution was 9.13.

The total acid neutralizing power (ANP) and rate of acid neutralization (RAN) of this solution after 1 week and 4 months at room temperature and after 1 additional month at 5, 25 and C. are given as follows:

Total ANP RAN. 1 ml. 0.1N HCl per 3.0 ml. ml. (LIN H at minutes pH HCl/ml. 2.5 5.0 7.5 10.0 12.5 15.0

1 wk..r.t. 9.13 46.7 49.0 49.6. ,5 0.6 50.7.

4 mOS.. m. 9.0 23.2 34.2 37.6 38.4 39.6 40.2 40.6

+1 mo.. 5C. 9.2 39.0 44.0 46.6 47.8 48.8 49.2

RAN. 1 ml. 0119 HC] t. 3.0 ml. EXAMPLE 4 I at minutes v 2.5 5.0 7.5 I I 10.0 12.5. 15.0 An aqueous antacid solution comprising polymeric me lumine-sorbitol-aluminumh dr xi 0 v- 3 wks.. m. 57.4 61.6 63.0 64.6 g y 0 de Omplex The above 1.0M Al 0.45Mg isopropoxide solution in cyclohexane was prepared as follows: A 7.1 19kg. por-j tion of magnesium aluminum isopropoxide was dising mole ratios of ,Alzsorbitolzrneglumine l:1.333:0.20 was prepared using aluminum ethoxide as follows: To a well stirred solution containing. 17.33 g. of percent sorbitol, 5.0 ml. of 2 M meglumine and 10 ml. of water was added 43.1 ml. ofa 1.16M solution of aluminum ethoxide in benzene. Stirring was continued for approximately 20 minutes after addition of the alkoxide. Stirring was stopped and the mixture was al lowed to separate. The solvent later was decanted and the aqueous phase was transferred to a tared 250 ml. round bottom flask using 5075 ml. of water. The residual benzene and the by-product ethanol were distilled 8 mine solution. The resulting solution was practically clear when made, having. only a very slight haze which cleared up on standing 3 days at room temperature.

The rates of acid neutralization (RAN) of the solutions of Example 1 and Examples 4-9 inclusive after 15 days at room temperature are given as follows:

RAN. 1 ml. (MN HC1 per 3.0 ml.

off under reduced pressure. The remaining thick syrn minutes upy residue was diluted to a volume of 65.0 g. net with Example 2.5 5.0 7.5 10.0 12.5 15.0 dlstilled water to yield a cloudy solution WhlCll gradu- 221 29.8 357 40.2 43.5 461 ally cleared up while standing at room temperature 6" 32,7 31,3 37,7 42.4 46.3 4&7 s" 24.7 35.3 41.5 45.8 49.2 51.4 over a period of about 2 weeks. 3 2 8 36] 40.9 43.7 4622 .2.0 .1. 43.9 47.3 49.4 51.5 EXAMPLE 5 7" 32.4 40.4 45.4 49.3 52.2 54.3 9" 32.0 39.8 45.4 48.8 51.3 53.9 An aqueous antacid solution comprlsing polymeric meglumine-sorbitol-aluminum hydroxide complex havs n ratio f :0- "Alzmcglumine ratio of 110.4. mg mole ratios of Alzsorbitolmeglumme of l:1.333:0.40 was prepared according to the procedure described in Example 4 but using 10.0 ml. of 2 M meg- 2O EXAMPLE 1O lumine solution and 5.0 ml. of water. The resulting so- A Solution like that of Example 1 was prepared using lutlon was p f y Clear made, havmg only a cyclohexane instead of benzene as a solvent and the Sllght haze which Cleared P on in about a weekfollowing ingredients per 1500 ml. of solution: 1 154 ml. of 1 M aluminum isopropoxide in cyclohexane. 400 g. EXAMPLE 6 of 70 percent sorbitol solution, 45 g. of meglumine and An aqueous antacid solution comprising polymeric 220 ml. of distilled water. After removal in vacuo of the meglumine-sorbitol-aluminum hydroxide complex havresidual cyclohexane and isopropyl alcohol, the reing mole ratios of Al:sorbitol:meglumine of maining material was diluted to 1500 ml 1644 g.) with l:l.333:0.20 was prepared as in Example 4 but using distilled water to yield a solution ofpolymeric meglu- 535 ml. of a 0.935 M solution of aluminum Z-butoxide mme-sorbiwl-alummurn hydroxlqe Complex having in cyclohexane The fi l Solution was cloudy, but mole ratios ofA1:sorb1tol:meglum1ne of 1:1.333:0.20. cleared while standing at room temperature over a 2 week period.

EXAMPLE 7 Analysis (wt./vol.): 7r Calcd. 7: Found An aqueous antacid solution comprising polymeric Mas AKOH)a (L0 552 meglumine-sorbitol-aluminum hydroxide complex havsorbimk meglumine 3.0 3.01 mg mole ratios of Al:sorbitol:meglumine of 1:1.333:0.40 was prepared using aluminum 2-butoxide following the procedure described in Example 6 but Th t tal acid neutralizing power (ANP) and rate of using 10.0 ml. of 2 M meglumine solution and 5 ml. of acid neutralization (RAN) of this solution after 1 water. The resulting solution was clear when made. month at room temperature are given as follows:

Total ANP RAN, 1 ml. 0.1N HC1 per 3.0 ml. ml. 0.1N at minutes HC1/ml. 2.5 5.0 7.5 g 10.0 12.5 15.0 20.0 30.0

1 mu. m. 24.4 15.4 20.4 24.2 27.2 29.6 31.4 34.6 39.0

ple 8 EXAMPLE 11 An aqueous antacid solution comprising polymeric meglumine-sorbitol-aluminum hydroxide complex having mole ratios of Al:sorbitol:meglumine of EXAMPLE 9 An aqueous antacid solution comprising polymeric meglumine-sorbitol-aluminum hydroxide complex having mole ratios of Al:sorbitol:meglumine of 1:1.333:O.4O was prepared following the procedure described in Example 8 but using 10 ml. of 2 M meglu- A solution like that of Example 2 was prepared using the following ingredients per 1500 ml. of solution: 410.2 rnl. of2.05M Al 0.95M Mg isopropoxide solution in cyclohexane, 25.1 ml. of 1 M aluminum isopropoxide in cyclohexane. 430.7 ml. of cyclohexane, 338 g. of percent sorbitol solution, 33.8 g. of meglumine and 486 ml. of water. After removing the residual cyclohexane and isopropyl alcohol by distillation in vacuo, the remaining solution was diluted to 1500 m1. (1643 g.) with distilled water to yield a solution of polymeric meglumine-sorbitol-aluminum hydroxide-magnesium hydroxide complex having mole ratios of Al:Mg:sorbitolzmeglumine of 1:0.45: l .50:O.20.

The total acid neutralizing power (ANP) and rate of acid neutralization (RAN) of this solution after 3 weeks at room temperature and'after additional storage in ml. ampoules for various times and temperatures are given as follows:

305.3 ml. of 1M Al isopropoxide incyclohexane, 273.5 ml. of 2.05M Al 0.95M Mg isopropoxide solution i n cyclohexane, 287 ml. of cyclohexane, 338 g. of 70 percent sorbitol solution, 33.8 g. of meglumine, 53.9 g. of magnesium gluconate and 260 ml. of distilled water. After removal of the residual cyclohexane and isopropyl alcohol, the remaining solution was diluted to 1500 ml. (1650 g.) with distilled water to yield a solution (pH of 9.30) of polymeric meglumine-sorbitolaluminum hydroxide-magnesium hydroxide complex having mole ratios of A1:Mg::sorbitol:meglumine of 1:0.30: 1.50:0. and also 0.15 mole of magnesium gluconate per mole of A].

Total ANP RAN. I ml. 0. IN HCl per 3.0 ml.

ml. 0.1N at minutes HCl/ml. 2.5 5.0 7.5 10.0 12.5 15.0 20.0 30.0

3 wks.. m. 26.0 52.4 60.0 62.4 63.4 64.2 65.0 66.0 67.2 4 wks.. 90C. 23.0 30.9 37.3 39.3 40.8 42.0 43.5 44.9 8 \\ks., C. 40.3 49.8 54.5 57.0 58.4 59.4 3 mos.. 25C. 54.2 60.2 62.4 63.7 64.5 65.1

The above 2.05M Al 0.95M Mg isopropoxide solution in cyclohexane was prepared by dissolving 2.36 kg. 25 Analysis (wt./vol.): 7: Calcd. 7: Found of magnesium aluminum isopropoxide (9.14 percent A] and 3 74 ercent M b assa in c clohexane and then A] as AKOH) P g y y y Mg as Mg(OH) 1.5 1.36

adding cyclohexane to achieve total volume of 4.0 11- meglumine 2.25 2.17 ters. The solution was assayed for Al and Mg and found i l8 to contain 2.05M Al and 0.95M Mg. 0 gluconic acid 3.4

EXAMPLE 12 A solution like that of Example 2 was prepared using the following ingredients per 650 g. (595 ml.) of solu- "snrbilol gluconic acid: sec Example 29 for analysis of each.

The total ANP and RAN ofthis solution after 3 tion: 500 ml. of 0.5 M magnesium dialuminum octaiso- 5 weeks at room temperature and additional storage in 5 propoxide in benzene, 173.35 g. of percent sorbitol ml. ampoules for various times and temperatures are solution, 50 ml. of 2 M meglumine solution and ml. given as follows:

Total ANP RAN, 1 ml. 0.1N HCl per 3.0 ml.

ml. 0.1N at minutes HCl/ml. .5 5.0 7.5 10.0 12.5 15.0 20.0 30.0

3 wks., m. 24.4 40.2 46.0 46.4 46.8 47.2 48.2 48.6 49.6 1 wk.. C. 13.6 18.9 23.2 26.0 28.3 30.3 33.0 36.0 4 wks.. 50C. 27.0 35.0 38.8 41.1 42.2 43.3 44.3 45.8 4 wks. 70C. 13.2 18.2 22.5 26.0 28.3 30.4 33.1 36.5 8 wks.. 50C. 22.8 31.2 36.1 38.3 39.9 41.1 43.0 3 mos., 25C. 40.4 44.8 46.7 g 47.5 48.1 49.0 50.0

of distilled water. After distilling off in vacuo the resid- EXA PLE 14 ual benzene and isopropyl alcohol, the remaining material was diluted with distilled water to yield 650 g. of solution. A 225 g. portion of this solution was diluted with 75 g. of distilled water and tested for RAN as follows:

A solution like that of Example I was prepared as in Example 1 using mannitol in place of sorbitol and the following ingredients per 130 g. of solution: ml. of

RAN. l ml. 0.1N HCl per 3.0 ml.

at minutes 7 (15.. m. 62.0 65.8 67.0 9 ds., M. 9.23 61.6 64.9 65.9 66.5 66.9 67.1 I25 ds.. r.t. 9.65 58.3 63.9 66.0 66.8 67.3 67.4 128 ds.. m. 9.68 57.4 63.4 65.2 66.3 67.2 67.6

EXAMPLE 13 65 1M aluminum isopropoxide in benzene, 24.27 g. of

A solution like that of Example 3 was prepared using the following ingredients per 1500 ml. of solution:

mannitol, 10.0 ml. of 2M meglumine solution and 23 ml. of water. After removal of the benzene and isopropyl alcohol, the remaining material was diluted with .11 distilled water to yield 130 g. of solutio n' 'comprisii g polymeric megluminem nne -alumin fliy'droxid co'inplex' having "mole.raiiosof 'Alzmarinitlolzrnglumine l :1 333:0.20. Its RAN aftr 82 days' at roomtempen' ature was found 'to bea's follows:

A: "51" .HEXAMBLE 17 Aqueous antacid solution 9.0)-havirig mole ratios of Al:sorbitol:meglumine of 1 :0.667:0.2O was pre- I RAN! 1 m1i01NHC1 c m1. :at minutes pH. 2.5 -5.0. 7.55. I 10.0 12.52. 15.0 20.0 25.0 30.0 82t1s ..'r.1.' 8.85 186 6 2414 28.7 31.9 i "34.7 36.8 (39.8 *4214' 4418 The. aqueous antacidsolutions of Examples. .1 through 24, each of which comprises the polymeric meglumine-sorbitol-aluminum hydroxide complex hav- 128661 516 1.11 111}; "lp percent sorbitol solution, 5.0 ml. of 2M megluminesolution. 15.0 ml. of distilled water and 50.0 ml. of 1M aluminum isomg the mdlcated mole ratlos of Al:sorbitol:meglumine, I propoxide solution in benzene, and diluting with diswere prepared by following the procedure described in 1 tilled water to a total weight of 65 gasin Example 15. Example 1 but using the appropriate quantities of in- The RAN values of this solution-after 9 and 65 days at gredients as indicated. room temperature were found to be as follows:

1 RAN. 1 ml. 0.1N HCl per 3.0 ml.

" ut minutes 65 1.15.. m. I 11,7 19.0 26.3 .322 356 ,;.3 .5,, 4 10 v, 450. 47 .5 49.6

PLEIJ EX MPLE 1 1;.

Aqueous antacid solution (pl-l 931 );having mole ratios of Al:sorbitol:meglumine of 1:0.667:0.333 was prepared as in Example 1 using 8.66 g. o'f70 percent sorbitol solution, 8.33 ml. of 2 Mmeglumine'so1utio'n, 12.0 ml. 'of distilled water and 50.0 ml. of 1M aluminum isopropoxide'"inbenzene, and dilutin'g with distilled water to' a total weight of-65' gpafter removal of the benz'eneandisopropyl:alcohol in vacuoiThe RAN- values of this solution afterj9 and 65 days at room tem perature were found to be as follows:

An aqueous antacid solution (pH 9. 2 5) havin'g'mole ratios of Al:sorbitol:meglumine of l:0.833:0.333 was prepared as in Example 1 using 10.83 g. of 70 percent sorbitol solution, 8.33 n'i'lfof 2M meglumin'dsolution,

12.0 ml. of distilled waterand 50.0 1111,- of 1M alumi num isopropo'xi'de in benzeii'e, aha aim ng With dis'"- 4 RAN. 1 ml. 0.1N HCl per 3.0 m1.

. at minutes I pH 2.5 7.5 10.0 12.5 15.0 20.0 25.0- 30.0

9C1S..l.t. 9.0 32.6 41.0 46j'1'f 50.1 52:0; 53.8 57.2 59.2 60.6 ds..r.t. 9.0 25.6 31.4 36.8; 39.4 41. 44.1 47.5 49.8 51.8

RANJI ml. 0.1.N HCl per '50 ml.

at minutes pH 2.5 5.0 7.5 10.0 12.5 15.0 20.0 25.0 0.0.. 66 12.."E1. 8.6 24.6 29.8 33. 37.0' 39.6 41.8 545.4 4'78' "499 EXAMPLElp; V p Aqueous antacid so1ution (pl-l-'9;-l5.)- having mole r'atios of Al:sorbitol:meglumine of 1:0.667:0.25 was prepared as in Example 1 using 8.66 g. of 70 percent sorbitol solution, 6.25 ml. of 2M meglumine solution, 14.0 ml. of distilled water and 50.0 ml. of 1M aluminum isopropoxide solution in benzene, and diluting with distilled water to a total weight of 65 g. as in Example 15. The RAN values of this solution after 9 and 65 days at room temperature were found to be as follows:

RAN. 1 ml. 0.1N HCl per 3.0 ml.

7 at minutes 7 94;.. 1 91 29.7, 39.2 43.6 46.9" A 49.2" 51.2 53.5 56.0 57.6 I 65x15. 1.1. I 818 21.5 27.7 35.8 38.2" 40.6 46'.8"f49. 1-f

RAN. 1 ml. (UN HCI per 3.0 ml. a 4 1 at rninutes V pH 2.5 5.0 7.5 I 10.0 K 2.5 15.0 20.0 25.0 30.0

66 ds.. m. 14.72 20.0 26.1 30.2 3'3'7' 36.3 38.4 42.2 44.6 49.0

solution in benzene, 52 g. of.70,percent sorbitol, ml.

EXAMPLE 20' Aqueous antacid solution having mole. ratios of Al:sorbitol:meglumine of l:1.0:0.50 was prepared as in Example 1 using 200 ml. of 1M aluminum isopropoxide solution in benzene. 52 g. of 70 percentsorbjtol, 50 ml. of 2M meglumine solution and 18 ml. ofdistilled water, and diluting with distilled water to a total weight of 260 g. after removal of the benzene and isopropyl alcohol. On analysis the percentages (wt/wt.) of aluminum as of 2M meglumine solution and 48 ml. of distilled water, and diluting with distilled water to a total weight of 260 g. after removal of the benzene and isopropyl alcohol. On analysisthe percentages (wt/wt.) of aluminum as Al(Ol-l),-,. sorbitol and meglumine were found to be 5.5, 13.7 and 3.1 1, respectively. The specific gravity of this solution at C. was found to be 1.0944 g./ml. lts ANP and RAN after 4 months at room temperature were 15 found to be as follows:

Total ANP RAN. 1 ml. 0.1N HCl per 3.0 ml.

ml. 0.1N at minutes HCl/ml. 2.5 5.0 7.5 10.0 12.5 15.0 20.0 25.0

4 mos... r.t. v 26.2 15.4 20.0 23.6 26.4 29.2 31.6 34.6 37.8

A1(OH):1. sorbitol and meglumine were found to be 5.5, EXAMPLE 23 14.2 and 7.58, respectively. The specific gravity of this solution at 25C. was found to be 1.1084 g./ml.' It's'ANP and RAN after four months at room temperature were found to be as follows:

Aqueous antacid solution having mole ratios of Alzsorbitolzmeglumine of 131502020 was prepared as 25 in Examplel using 100 ml. of 1M aluminum isopropox- Total ANP RAN, .1 0.1151 HCl per 3.0 ml.

ml. 0.1N at minutes HCl/ml. 2.5 5.0 7.5 10.0 12.5 15.0 20.0 25.0

EXAMPLE 21 ide in benzene, 39.0 g. of 70 percent sorbitol solution.

Aqueous antacid solution having mole ratios -of 10 m1. of 2M meglumine solution and 10 ml. of distilled water, and diluting with distilled water to a total weight of 130g. The RAN values of this solution after 1, 8, l6

Al:sorbitol:meglumine of 1:1.0:O.333 was prepared as in Example 1 using 200 ml. of 1 M aluminum isopropoxand 106 days at room temperature were found to be as ide solution in benzene, 52 g. of percent sorbitol, follows: 1

RAN. 1 ml. 0.1NHC1 per 3.0 m1.- 1 o I at minutes pH 2.5 5.0 7.5 10.0 15.0 20.0 25.0 v 30.0

1 d.. m. 8.55 34.0 48.0 53.8 57.3 59.4 60.8 63.5 65.0 66.0 8 ds.. r.t. 8.5 25.3 30.0 43.6 49.0 52.5 55.2 59.2 61.6 63.2 16 (15.. r.t. 20.9 28.1 33.6 37.8 41.2 43.7 47.7 52.3 52.8 106 05.. 1.1. 8.4 14.8 19.5 22.6 25.6 28.3 30.6 34.4 37.3 39.7

33.3 ml. of 2M meglumine solution and 34 ml. of dis- EXAMPLE 24 tilled water, and diluting with distilled water to a total Aqueous antacid solution having mole ratios of weight of 260 g. after removal of he enzene nd i Alzsorbitolzmeglumine of 1:2.0:O.20 was prepared as in propyl alcohol. n analysis th P g s t/ t) f Example 1 using 100 ml. of 1M aluminum isopropoxide aluminum as Al(OH).1. sorbitol and meglumine were 50 solution in benzene, 52 g. of 70 percent sorbitol, 10 m1.

found to be 5.7, 13.1 and 5.18, respectively. The specific gravity of this solution at 25C. was found to be 1.1012 g./ml. Its ANP and RAN after 4 months at room temperature were found to be as follows:

and diluting with distilled water to a total weight of g. The RAN values of this solution after 1, 8 and 106 days at room temperature were found to be as follows:

Total ANP .RAN. 1 m1. 0.1N HCl per 3.0 m1.

ml. 0.1N at minutes HCl/ml. 2.5 5.0 7.5 10.0 12.5 15.0 20.0 25.0

4 mos. r.t. 25.4 20.6 25.4 29.0 r 31.4 33.8 35.6 38.4 40.8

RAN. 1 ml. 0.1N HCl per 3.0 ml.

at minutes 1 d.. r.t. 8.7 37. 3 48.2 54.1 57.6 60.1 61.9 64.2 67.0 8 11s., r.t. 8.5 25.0 35.5 42.0 46.1 49.0 51.4 54.6 57.3 59.1 106 (15.. r.t. 8.29 14.6 18.8 22.2 24.9 27.4 29.3 32.8 35.7 38.1

EXAMPLE 22 The aqueous antacid solutions of Examples 25 Aqueous antacid solution having I mole ratios of Alzsorbitolzmeglumine of l:1.'0:0.20 was prepared as in Example 1 using 200 ml. of 1M aluminum isopropoxide through 28, each of which comprises the polymeric meglumine-sorbitol-aluminum hydroxide-magnesium hydroxide complex having the indicated mole ratios of Al:Mgzsorbitolzmeglumine, were prepared following of 2M meglumine solutionand 10 ml. of distilled water,

the procedure described in Example 2 using the appropriate quantities of ingredients as indicated.

EXAMPLE 25 Aqueous antacid solution (pl-1 9.75) having mole ratios of AlzMgzsorbitolzmeglumine of 1:0.40:1.50:0.20 was prepared as in Example 2 using 88.9 ml. of 1M Al 0.45M Mg isopropoxide solution in cyclohexane. l 1.1 ml. of 1M Al isopropoxide solution in cyclohexane, 39.0 g. of 70 percent sorbitol solution, 10.0 ml. of 2M meglumine solution and 30 ml. of distilled water, and diluting with distilled water to a total weight of 168 g. after removal of the cyclohexane and isopropyl alcohol in vacuo. 1

was prepared as in Example 2 using 20 ml. of 0.5M magnesium aluminum isopropoxide in benzene, 30 ml. of 1M aluminum isopropoxide in benzene. 17.33 g. of 70 percent sorbitol solution, 5 ml. of 2M meglumine solution and 8 ml. of distilled water. and diluting with water to a total weight of 65 g. after removal of the benzene and isopropyl alcohol in vacuo. A 26.5 g. portion of this aqueous antacid solution was diluted with distilled water to a total weight of 30 g. to produce a solution having a total acid neutralizing power equivalent to 6 percent of aluminum hydroxide. The RAN of this solution after 173 days at room temperature was found to be as follows:

RAN. 1 ml. 0.1N HCl per 3.0 ml.

EXAMPLE 26 Aqueous antacid solution (pH 9.75) having mole ratios of AlzMgssorbitolzmeglumine of 1:0.30:1.50:0.20 was prepared as in Example 2 using 66.7 ml. of 1M Al 0.45M Mg isopropoxide solution in cyclohexane, 33.3

ml. of 1M Al isopropoxide solution in cyclohexane, 39.0 g. of 70 percent sorbitol solution, 10.0 ml. of 2M meglumine solution and 30 ml. of distilled water, and diluting with distilled water to a total weight of 168 g. after removal of the cyclohexane and isopropyl alcohol in vacuo.

EXAMPLE 27 Aqueous antacid solution (pH 9.12) having mole ratios of AlzMgzsorbitolzmeglumine of 1:0.10:1.33:0.20

was prepared as in Example 2 using 10 ml. of 0.5M magnesium aluminum isopropoxide in benzene, ml. of 1M aluminum isopropoxide in benzene, 17.33 g. of 70 percent sorbitol solution, 5 ml. of 2M meglumine solution and 8 ml. of distilled water, and diluting with 40 Aqueous antacid solution comprising polymeric meglumine-sorbitol-aluminum hydroxide-magnesium hydroxide complex having the same mole ratios of ingredients as the solution of Example 3 was prepared following the procedure of Example 3. lts pH was 9.2 and its analysis was as follows:

Calculated Found 7r. \\'t./vol. 7r \\'t./vol.

aluminum as Al(OH);1 4.5 4.57 total magnesium as Mg(OH): 1.5 1.49 meglumine 2.25 2.24 sorbitol 15.8 15.5 gluconic acid 3.4 3.2

The total acid neutralizing power (ANP) and rate of acid neutralization (RAN) of this solution after one month at 5, 25 and C., and three months at 25 and 50C. are given as follows:

Total ANP RAN. 1 m1. 0.1N HCl per 3.0 ml.

ml. 0.1N at minutes pH HCl/ml. 2.5 5.0 7.5 10.0 12.5 15.0

1 1110.. 5C. 9.2 24.8 50.4 53.6 55.2 56.2 57.0 57.4 1 m6.. 25C. 9.2 24.8 47.8 51.6 53.2 54.4 55.0 55.6 1 "10.. 50C. 9.1 24.0 30.8 39.4 43.2 45.0 46.0 47.0 3 mos. 25C. 9.2 24.4 42.8 47.6 49.6 50.8 51.6 52.2 3 11105.. 50C. 9.2 23.6 23.6 32.6 37.4 40.6 42.8 44.0

distilled water to a total weight of 65 g. after removal 50 EXAMPLE 30 of the benzene and isopropyl alcohol in vacuo. A 28.15 g. portion of this aqueous antacid solution was diluted with distilled water to a total weight of 30 g. to produce a solution having a total acid neutralizing power equivalent to 6 percent aluminum hydroxide. The RAN of this solution after 173 days at room temperature was found to be as follows:

Aqueous antacid solution comprising polymeric meglumine-sorbitol-aluminum hydroxide complex having the same mole ratios of ingredients as the solution of Example 1 is prepared following the procedure of Example 1 using aluminum n-propoxide in place of aluminum isopropoxide.

RAN. 1 ml. 0.1N HCl per 3.0 ml.

at minutes 173 ds.. r.t. 9.38 30.7 39.4 44.7 48.4 50.2 52.4 54.8

EXAMPLE 28 EXAMPLE 31 Aqueous antacid solution (pH 9.33) having mole ratios of AliMgzsorbitol:meglurriine of 1:0.20:1.33:O.20

Aqueous antacid solution comprising polymeric meglurnine sorbitol-aluminum hydroxide complex having mole ratios of Alzsorbitolzmeglumine of 1:0.50:O.40

is prepared following the procedure described in Example 1 using corresponding molar equivalent quantities of the reactants.

EXAMPLE 32 Aqueous antacid solution comprising polymeric meglumine-sorbitol-aluminum hydroxide having mole ratios of Alzsorbitolzmeglumine of 1:0.333:0.40 is prepared following the procedure described in Example 1 using twice as much meglumine and one-fourth as much sorbitol as in Example 1.

EXAMPLE 33 A solution like that of Example 2 was prepared using the procedure of Example 2 but using aluminum magnesium n-propoxide in place of aluminum magnesium isopropoxide as the source of magnesium. The following ingredients were used per 500 ml. of solution: 288 ml. of 1.0M Al 0.45M magnesium propoxide (propoxide. as used here is generic to n-propoxide and isopropoxide since it was prepared from aluminum magnesium n-propoxide and aluminum isopropoxide by the procedure given hereinbelow) solution in cyclohexane, 1 12.5 g. of sorbitol solution, l 1.3 g. of meglumine and 160 ml. of distilled water. There was thus obtained a solution (pH 9.7) comprising polymeric megluminesorbitol-aluminum hydroxide-magnesium hydroxide complex having mole ratios of Al:Mg:sorbitol:meglumine of 1:0.45:l.50:0.20. The total acid neutralizing power (ANP) and rate of acid neutralization (RAN) of this solution was found to be as follows:

reflux. After three hours of refluxing, practically all of the metal had reacted. The refluxing was continued for another 2 hours. The reaction mixture was then distilled and about 70 ml. of distillate was collected, the temperature of the reaction mixture rising from about 135C. at the start of distillation to about 165C. To the remaining material was added 500 ml. of cyclohexane and the solution was allowed to cool. When the solution had started to gel on cooling, 45 ml. of n-propanol was added. Additional cyclohexane was added to give a volume of about 900-950 ml. The solution was treated with dry infusorial earth and decolorizing charcoal, and the mixture filtered. The filter pad was washed with cyclohexane. The combined filtrate and washings were brought to a volume of one liter by adding cyclohexane. On assay this solution was found to contain 1.00M Al and 0.50M Mg which were the same as the calculated values.

EXAMPLE 34 A solution like that of Example 3 was prepared using the procedure of Example 3 but using aluminum magnesium n-propoxide in place of aluminum magnesium isopropoxide as the source of magnesium. The follow ing ingredients were used per 500 ml. of solution: 288 ml. of 1.0M Al 0.3M Mg propoxide solution in cyclohexane (preparation of this solution of a mixture of npropoxide and isopropoxide is given hereinbelow), 1 12.5 g. of sorbitol solution, 1 1.3 g. of meglumine, 130 ml. of water, and 18.0 g. of magnesium gluconate in 72 Total ANP RAN. I ml. 0.1N HCl per 3.0 ml.

ml. 0.1N at minutes HCl/ml. 2.5 5.0 7.5 10.0 12.5 15.0 20.0

ml. of water. There was thus obtained a solution (pH 9.48) comprising polymeric meglumine-sorbitolaluminum hydroxide-magnesium hydroxide complex having mole ratios of AlzMgzsorbitolzmeglumine of 1:0.30:1.50:0.20 and also 0.15 mole of magnesium gluconate per mole of Al. The total ANP and RAN of this solution were found to be as follows:

Total ANP RAN, 1 ml. 0.1N HCl per 3.0 ml.

ml. 0.1N at minutes HCl/ml. 2.5 5.0 7.5 10.0 12.5 15.0 20.0

Said 1.0M Al 0.5M Mg n-propoxide solution in cyclohexane was prepared as follows: Under anhydrous conditions a mixture containing 100 ml. of n-propanol and 5 g. of purified aluminum metal (8-20 mesh) with 4 g. of magnesium aluminum isopropoxide as catalyst was heated with stirring to reflux the alcohol. After the reaction had started in about 5 to 10 minutes, heating was reduced while maintaining a slow reflux. After about 30 minutes of refluxing with stirring, a further 22 g. portion of aluminum metal (8-20 mesh), 12.16 g. of magnesium metal turnings, and another 100 ml. portion of n-propanol was added; and, heating was increased to bring the alcohol to reflux. After the exothermic reaction had started, external heating was stopped. After about fifteen minutes of refluxing, a further 200 ml. portion of n-propanol was added and the stirred reaction mixture was heated to produce a gentle The above intermediate 1.0M A10.3M Mg propoxide solution in cyclohexane was prepared by mixing 210 m1. of 1.0M A1 0.5M Mg n-propoxide solution in cyclohexane (preparation given above in Example 33) and ml. of 1.4M A1 isopropoxide solution in cyclohexane, and adding enough cyclohexane to bring the volume to 350 ml.

Satisfactory solutions were obtained when the above solutions were further diluted with distilled water, e.g., when a given volume of each solution of Example I, 2 or 3 is mixed well with an equal volume of distilled water, said diluted solutions have about 12 to 14 percent by weight per volume of the respective complex.

COMPARATIVE lNTRAGASTRlC BUFFERING EFFECTS IN THE ALERT DOG The aqueous antacid solution of the instant invention when.compared with a commercial antacid suspension hen ading about 4 percent each of aluminum hydroxid e and' magnesium hydroxide and about l perc ent ofsorbitol (hereinafter designated as Corn. SuSpI No. l')' in unanesthetized mongrel dogs with normal secretory/activity. Details and results of this studyare pre s ented'he re inbelow.

Preparation of Animals Five normal male mongrel used in this experiment. Each animal had anendfo tra"- cheal cannula inserted urider routine'as'eptic conditions and using barbital sodium anesthesia. Ther'ifundei sur gical anesthesia, a stainless steel Thomas cannula was inserted such that the greater gastric curvature was made accessible to the exterior by, means ofstl fi cannula. After recovery from the operative-procedure the animal was trai'ned-tost'and in a Pavlov=framie for 3 to 4 hours and permit the insertion of tubes andoth'erappurtenances intothe gastric cavity, and w'as psychologically prepared to accept and tolerate, the technical teamwithout untoward effects on thesec rletory physi ology of the stomach. Prepared animalswere restricted from inclusion in'the study if the basal -intragastric.pH was not less than 3.0, if the intragastric pH did not rise to at least 3.0 after the administration of antacid, or if the intragastric pH remained above 3.5 for more than 60 minutes after administration of the antacid. These instances are believed to represent technical difficulties rather than reflecting normal physiological intragastric responses. I v I v I Technique for Testing Each dog was fasted for 24 hours (water ad."lib.').be'- fore the. start of testing. The animal was thenplaced "in a Pavlov frame and a naso-gastric tube was inserted into the dependent portion of the stomach via the Thomas cannula. The stomach contents were evacuated and retained to constitute the basal gastric analysis data. The animals were permitted to control their salivary secretions in a normal physiological manner. A pH electrode was inserted into the gastric vault via the Thomas cannula and readingsiwere noted a't minute intervals. Samples of gastric juice were aspiratedat 5 minute intervals and measured as to volurne pH; and total acid (assessed by titrimetric means using l.0 N NaOH and a phenol red indicator). The basal'studieswere continued for 30 minutes with pH less thanfi .0 for at least three consecutive 5 minute period s. Fifteen mls. of the antacid were then introduced injto the stoniach though the naso-gastric, tube wasjfflushe d with air equal in volumeto the dead .spaceof the tube. The intragastric pH was noted and Ia 3 ml. sample ,of gastric juice was obtained at 2 minute intervals for minutes. One ml. of the fluid was retainedjfor analysis and theremainder returned to the gastric vault using an air flush. Thereafter, at'5 minute"int'er'v'als,"similar studies were carried out until the intragastric pH returned to the basal level but in any event was less than 3.0. A

SQ ninute basalperiodthen ensued wherin the gastric contents were evacuated every 5 rr'iinutes. measured,

and analyzed as previously outlined. The experiment was then repeated exactly using the second antacid.

"As Ex.3 (A) and Com. Susp.:No. l (CS)were administered to each of the five test dogs in the following order: A-JC S CS-A. i

Thedata obtained in this study are presented in Table I. These data indicate that A s Ex. 3 produceda more intense, more prolonged and more consistent antacid effect than Com. Susp. No.1 when administered to alert dogs with normal secretory activity.

Tablel of A's Ex. 3' and Com.- Susp. No. l v

' lntragastric Effects in the Alert Dog I A's EX. 3"

Dog/Test Area" Time pH Peak pH No. 1 2 Over 3.5

(Minutes) 2A 3.1 l 44 7.4 2D 1.83 40 7.6 3A 2.43 48 7.5 A 3D v 2.67 49 a0 4A 4.77 76 6.8 4D 4.30 71 5A 2.04 48 6.6

Com. Susp. No. l g V Dog/T est Area" Time pH Peak pH No. Over 3.5

(Minutes) 113 0.44 14 6.8 1C 0.76 29 6.4 213 0.71 29 6.8 2C I V 0.80 24 6.5 3B 1.12 28 6.5 3C 1.02 29 6.3 43 33 61 4C 0.80 24 6.5 '5B 1.36 33 5.9 5C" 1.55 44.; 6.2

"A standard l5 ml. dose was used at all times. "Area (in arbitrary units) under the curve described by plotting intragastric pH above 3.5 versus time in minutes.

COMPARATIVE ANTACID AND ANTIULCER ACTIVITIES IN RATS.

n The aqueous antacid solution offthe' invention was found to inhibit significantly gastric ulceration in reserpinize d rats and, in fact, preferred embodiments were found to be more active than either of two commercial antacid suspensions in protecting rats fromreserpineinduced ulcers. In this study applicants aqueous'antacid solutions of Examples 1, l0, l l, l2 and l 3 (hereinafter designated, respectively, as -As Ex. 1, As Ex. 10, As Ex. ll, As Ex. l2and-As Ex. 13) were compared with one commercial aluminum hydroxide- Method Male, Sprague-Dawley albino rats weighing approximately 300 g. were fasted 48 hours with water supplied ad libitum. Then, the rats, in groups of seven, were medicated orally with the above said antacids in a volume of 1.5 ml./kg. hourly for 6 hours (6x in 6 hours). A control group of 10 rats received a volume of 1.5 ml./kg. of distilled water in the same manner. All antacids were diluted to a l :2 concentration with distilled water prior to intubation. Immediately following the first medication. the control rats and all medicated rats were injected intramuscularly with 5.0 mg./kg. of reserpine in a volume of 1.0 ml./kg. to induce ulcers. At the end of the 6 hour period, the rats were sacrificed, and the stomachs were removed, opened along the greater curvature, and examined for number and size of ulcers. An ulcer index was determined for each rat according to the size and number of ulcers per rat.

Size of Value of Ulcer Ulcer 1 mm =1 (small) 1 mm 2.9 mm 2 (medium) 53 mm (large) The number of ulcers of each size in each stomach was multiplied by its respective value. The total value for all rats in each group was divided by the number of ratsper group for an average ulcer score. The mean ulcer indices of the medicated and control rats were compared and expressed as percent inhibition of ulceration.

Results Table II shows the effect of the tested antacids on the number and size of ulcers in comparison with the control rats. Applicants aqueous antacid solutions containing aluminum hydroxide and magnesium hydroxide, either with (As Ex. No. 13) or without (As Ex. No. 1 1 and As Ex. No. l2) the addition of magnesium gluconate, significantly inhibit gastric ulceration in rats. Applicants aqueous antacid solutions containing aluminum hydroxide with no magnesium hydroxide (As Ex. No. l and As Ex. No. inhibit gastric ulceration to a greater degree than the two commercial antacid suspensions.

Table ll EFFECT OF ANTACIDS ON ULCERS INDUCED IN RATS BY RESERPINE FURTHER COMPARATIVE ANTACID AND ANTIULCER ACTIVITIES IN RATS The aqueous antacid solution of Example 1 (As Ex. 1) was found to provide greater protection against ulcers in the nonligated reserpinized rat than five commercial aluminum hydroxide or aluminum hydroxidemagnesium hydroxide suspensions, namely, the abovenoted Com. Susp. No. l and Com. Susp. No. 2 and the following three commercial suspensions: an aluminum hydroxidegel (about 5,- p ercent aluminum hydroxide) stabilized with sorbitoland containing about 1.5 percent magnesium hydroxide (hereinafter designated as Corn. Susp. No. 3); an aluminum hydroxide gel (about 3.6 percent aluminum hydroxide) stabilized with sorbito] and containing about 2.8 percent magnesium hydroxide (hereinafter designated as Corn. Susp. No. 4); and, a suspension containing about 4.7 percent aluminum hydroxide and 3.4 percent magnesium hydroxide (hereinafter designated as Com. Susp. No, 5).

Method The test method was essentially like that already described her'einabove except that the rats were used in groups of eight. Two experiments were run in order to: 1) determine comparative ulcer protection of As Ex. l,Com. Susp. No. 3 and Com. Susp. No. 2; and (2) determine comparative ulcer protection of As Ex. 1, Com. Susp. No. 4, Com. Susp. No. l and Com. Susp. No. 5.

Results I Tablelll shows that A 3 Ex. 1,.Com. Susp. No. 3 and Corn. Susp. No. 2 when administered at a 1:2 dilution provided effective protection against reserpineinduced gastric ulcers. A's Ex. 1 provided better protection (94 percent) than did C'om. Susp. No. 3 percent) and Corn. Susp. No. 2 (68 percent). Seven of the eight control rats had a total of 57 ulcers, whereas only two of the eight rats receiving As Ex. 1 had a total of four ulcers. Five of-the eight rats receiving either Corn. Susp. No. 3 or Corn. Susp. N0. 2 had a total of 19 ulcers each. The ulcer score, which was indicative of both the total number of ulcers and the size of the ulcer, was 8.8, 0.5, 3.5 and 2.8' for the control, As Ex. 1, Com. Susp. No. 3 and Com.'Susp. No. 2 groups respectively. f v

Av. No.

Size of Ulcers No. Uleer Ulcers/ Ulcer /r Antacid Sml. Med. Lg. Total JICL! Rats Rat Score lnhib.

Control 57 l() (l 67 9/10 6.7 7.7 A's Ex. 1 l 6 (l (J 6 3/7 0.9 0.9 88" A's Ex. l0 l8 0 18 5/7 2.6 2.6 66 As Ex. 1" 28 (l 0 28 6/7 4.0 4.0 48 A's Ex. l3 l0 3 0 l3 6/7 1.9 2.3 70" A's Ex. 12" 8 (J O 8 4/7 1.1 1.1 86" Com. Susp. NlLl 3] 3 O 34 7/7 4.9 5.3 3] Com. Susp. No.2 13 l 2 16 6/7 2.3 3.6 53

"After extended storage at room temperature. "After extended storage at room temperature. Students "1 test; significance hctueen means: P UMS.

Table III Effect of Antacids on Ulceration in Non-Ligated Rats Total Av. No. No. of No.ulccr- Ulcers/ Ulcer /1 Antacid Dilution Ulcers ated Rats Rat Score lnhihv Control 57 7/8 7.1 8.8 A's Ex. 1 1:2 4 2/8 (1.5 0.5 )4 Com. Susp. No.3 1:2 19 5/8 2.4 3.5 60 Com. Susp. No.2 1:2 24 2.8 68

Table IV which contains average data of two separate experiments run in duplicate, s ows that 16 control rats developed a mean total of 1 7 ulcers with an ulcer score of 9.6. The same number of rats receiving As Ex. 1 had only 44 ulcers and a score of 3.1 with a 68 percent inhibition. Rats in the Com. Susp. No. 4 and Com. Susp. No. 1 groups had a total of 88 and 83 ulcers with a score of 5.7 and 5.9 respectively. Com. Susp. No, 5 afforded no protection. Sixteen rats receiving Com. Susp. No. 5 had a total of 134 ulcers and an ulcer score of 10.]. Seven large ulcers were produced in the Com. Susp. No. 5 group, two in the Com. Susp. No. 1 group and none in the Com. Susp. No. 4, As Ex. 1 and control groups.

Table IV tissue changes.

As Ex. 3

Acute oral toxicity (LD,-, determinations were carried out with As Ex. 3 and Com. Susp. No. l in the mouse and rat. The two samples were tested as a direct assay. The LDms for both As Ex. 3 (a solution) and for Corn. Susp. No. l (a suspension) in the mouse and rat were ml./kg. at 7 days. No pharmacologic symptoms or signs of toxicity were observed at any dose level of either As Ex. 3 or Com. Susp. No. l in the mouse or rat. On the seventh day after medication the mice and rats appeared normal and had gained weight. Autopsy of a respresentative number of mice and rats revealed no macroscopic tissue changes.

Effect of Antacids on Ulceration in Non-Ligated Rats (Average of Two Tests) In summary, these two experiments show that As Ex. 1 produced greater protection against ulceration in the non-ligated reserpinized rat than Com. Susp. Nos. 1, 2, 3, 4 and 5.

TOXICOLOGICAL STUDIES The following acute oral toxicological studies of applicants aqueous antacid solutions, As Ex. 1, As Ex. 2 and As Ex. 3, were carried out using standard toxicological test procedures. in mice and rats using ten animals per each dose level tested, i.e., 1O, 20 and 40 ml./kg.

As Ex. 1

An acute oral toxicity determination was carried out in mice with As Ex. I and was found to be 40 ml./kg. at 24 hours and 7 days. There were no deaths or untoward reactions at any of the three dose levels tested. On the seventh day after medication the mice appeared normal and had gained weight. Autopsy of some of these mice revealed no obvious tissue changes.

A's Ex. 2

Acute oral toxicity (LD,-, determinations were done with As Ex. 2 in the mouse and rat. The LD.-,0 was 40 ml./kg. in both the mouse and rat at 7 days. No pharmacologic symptoms or signs of toxicity or deaths were observed at any dose level of As Ex. 2 in either the mouse or rat. On the seventh day after medication the mice and rats appeared normal and had gained weight. Autopsy of a representative number revealed no gross PLASMA ALUMINUM AND MAGNESIUM CONCENTRATIONS IN RATS AFTER ADMINISTRATION OF ANTACIDS These studies ascertained plasma aluminum and magnesium concentrations in rats after administration of the five antacids: As Ex. 10, As Ex. 11, As Ex. 13, Com. Susp. No. 1 and Com. Susp. No. 2. The plasma levels of the actions were measured by atomic absorption spectrometry in rats given oral suspensions or solutions. Times of sampling were 2 and 5 hours. No significant change was seen in the levels of these substances relative to control animals receiving saline alone.

I claim:

1. A clear aqueous antacid solution having a pH from about 8.5 to 9.8 comprising water and an effective amount of a polymeric meglumine-hexitol-aluminum hydroxide complex which has mole ratios of Alzhexitolzmeglumine of about 1:0.333-1 .333:O.l2-O.5O where hexitol is sorbitol or mannitol.

2. A clear aqueous antacid solution having a pH from about 8.5 to 9.8 comprising water and from about 12 to 45 percent by weight per volume of a polymeric meglumine-hexitol-aluminum hydroxide complex which has mole ratios of Alzhexitolzmeglumine of about 1:O.3331.333:O.12O.5O where hexitol is sorbitol or mannitol.

3. The solution of claim 2 containing about 4.5 to 9.0 percent of aluminum as aluminum hydroxide, about 2.25 to 4.5 percent of meglumine and about 15 to 30 percent of sorbitol or mannitol, each percentage being as weight per volume.

4. The solution of claim 2 where said complex has mole ratios of Alzhexitolzmeglumine of about 1:0.667-l .333:O.20-0.333.

5. The solution of claim 2 where up to about 27 percent by weight of the aluminum hydroxide is replaced by magnesium hydroxide.

6. The solution of claim 5 containing about 4.5 to 9.0 percent of aluminum as aluminum hydroxide, up to about 3.0 percent of magnesium as magnesium hydroxide, about 2.25 to 4.5 percent of meglumine and about to 30 percent of sorbitol, each percentage being as weight per volume.

7. The solution of claim 6 containing up to about 7.0 percent weight per volume of magnesium gluconate.

8. The solution of claim 5 containing about 4.5 to 6.0 percent of aluminum asaluminum hydroxide, up to about 1.5 percent of magnesium as magnesium hydroxide, about 2.25 to 3.0 percent of meglumine and about 15 to percent of sorbitol, each percentage being as weight per volume.

9. The solution of claim 8 containing up to about 3.5 percent weight per volume of magnesium gluconate.

10. The solution of claim 1 where sorbitol is the hexitol.

11. The solution of claim 1 where mannitol is the hexitol.

12. A process for preparing a clear aqueous antacid solution having a pH from about 8.5 to 9.8 comprising water and from about 12 to 45 percent by weight per volume of a polymeric meglumine-hexitol-aluminum hydroxide complex which has mole ratios of Alzhexitolzmeglumine of about 1:0.333-1 .333:0.l2-O.50

where hexitol is sorbitol or mannitol, said process which comprises mixing aluminum tri-(loweralkoxide), where lower-alkoxide has from two to five carbon atoms inclusive, in a non-polar solvent with an aqueous solution containing said mole ratio proportions of meglumine and sorbitol or mannitol, separating the aqueous phase from the non-polar phase of the mixture, heating the aqueous phase under reduced pressure at about 4070C. to remove residual non-polar solvent and the lower-alkanol produced by the reaction, and diluting the remaining aqueous solution with water to the desired concentration.

13. The process of claim 12 for the preparation of the solution thereof wherein up to about 27 percent by weight of the aluminum hydroxide is replaced by magnesium hydroxide where the calculated proportion of the aluminum tri-(lower-alkoxide) is replaced by magensium di-(lower-alkoxide) or by magnesium dialuminum octa-(lower-alkoxide) where lower-alkoxide has from two to five carbon atoms inclusive.

14. The process of claim 12 where lower-a1koxide is isopropoxide.

15. The process of claim 12 where lower-alkoxide is n-propoxide.

16. The process of claim 13 where lower-alkoxide in each instance is isopropoxide.

17. The process of claim 13 where lower-alkoxide in each instance is n-propoxide.

18. The process of claim 12 where hexitol is sorbitol.

19. The process of claim 12 where hexitol is mannito].

20. The proces of claim 13 where hexitol is sorbitol.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3, 892, 851

DATED July 1, 1975 lNVENTOR( I Emil T. Hinkel, Jr.

it is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 2,

POLYMERIC "PLOYMERIC" should read Column 1, line 33, "l.333:0." should read l.333:0.20 and on line 34 omit "20-".

Column 2, line 20, "l.333:0.-" should read l.333:0.20- and on line 21 omit "20".

Column 4, line 8, "37+C." should read 37C.

Signed and Scaled this twenty-first D21) Of October 1975 [SEAL] RUTH C. MASON Arresting Officer C. MARSHALL DANN Commissioner of Patents and Trademarks 

1. A CLEAR AQUEOUS ANTACID SOLUTION HAVING A PH FROM ABOUT 8.5 TO 9.8 COMPRISING WATER AND A EFFECTIVE AMOUNT OF A POLYMERIC MEGLUMINE-HEXITOL-ALUMINUM HYDROXIDE COMPLEX WHICH HAS MOLE RATIOS OF AL:HEXITOL:MEGLUMINE OF ABOUT 1:0.333-1.333:0.12-0.50 WHERE HEXITOL IS SORBITOL OR MANNITOL.
 2. A clear aqueous antacid solution having a pH from about 8.5 to 9.8 comprising water and from about 12 to 45 percent by weight per volume of a polymeric meglumine-hexitol-aluminum hydroxide complex which has mole ratios of Al:hexitol:meglumine of about 1: 0.333-1.333:0.12-0.50 where hexitol is sorbitol or mannitol.
 3. The solution of claim 2 containing about 4.5 to 9.0 percent of aluminum as aluminum hydroxide, about 2.25 to 4.5 percent of meglumine and about 15 to 30 percent of sorbitol or mannitol, each percentage being as weight per volume.
 4. The soluTion of claim 2 where said complex has mole ratios of Al:hexitol:meglumine of about 1:0.667-1.333:0.20-0.333.
 5. The solution of claim 2 where up to about 27 percent by weight of the aluminum hydroxide is replaced by magnesium hydroxide.
 6. The solution of claim 5 containing about 4.5 to 9.0 percent of aluminum as aluminum hydroxide, up to about 3.0 percent of magnesium as magnesium hydroxide, about 2.25 to 4.5 percent of meglumine and about 15 to 30 percent of sorbitol, each percentage being as weight per volume.
 7. The solution of claim 6 containing up to about 7.0 percent weight per volume of magnesium gluconate.
 8. The solution of claim 5 containing about 4.5 to 6.0 percent of aluminum as aluminum hydroxide, up to about 1.5 percent of magnesium as magnesium hydroxide, about 2.25 to 3.0 percent of meglumine and about 15 to 20 percent of sorbitol, each percentage being as weight per volume.
 9. The solution of claim 8 containing up to about 3.5 percent weight per volume of magnesium gluconate.
 10. The solution of claim 1 where sorbitol is the hexitol.
 11. The solution of claim 1 where mannitol is the hexitol.
 12. A process for preparing a clear aqueous antacid solution having a pH from about 8.5 to 9.8 comprising water and from about 12 to 45 percent by weight per volume of a polymeric meglumine-hexitol-aluminum hydroxide complex which has mole ratios of Al: hexitol:meglumine of about 1:0.333-1.333:0.12-0.50 where hexitol is sorbitol or mannitol, said process which comprises mixing aluminum tri-(lower-alkoxide), where lower-alkoxide has from two to five carbon atoms inclusive, in a non-polar solvent with an aqueous solution containing said mole ratio proportions of meglumine and sorbitol or mannitol, separating the aqueous phase from the non-polar phase of the mixture, heating the aqueous phase under reduced pressure at about 40-70*C. to remove residual non-polar solvent and the lower-alkanol produced by the reaction, and diluting the remaining aqueous solution with water to the desired concentration.
 13. The process of claim 12 for the preparation of the solution thereof wherein up to about 27 percent by weight of the aluminum hydroxide is replaced by magnesium hydroxide where the calculated proportion of the aluminum tri-(lower-alkoxide) is replaced by magensium di-(lower-alkoxide) or by magnesium di-aluminum octa-(lower-alkoxide) where lower-alkoxide has from two to five carbon atoms inclusive.
 14. The process of claim 12 where lower-alkoxide is isopropoxide.
 15. The process of claim 12 where lower-alkoxide is n-propoxide.
 16. The process of claim 13 where lower-alkoxide in each instance is isopropoxide.
 17. The process of claim 13 where lower-alkoxide in each instance is n-propoxide.
 18. The process of claim 12 where hexitol is sorbitol.
 19. The process of claim 12 where hexitol is mannitol.
 20. The proces of claim 13 where hexitol is sorbitol. 